atrial-natriuretic-factor and Nephrotic-Syndrome

The pathologic consequences of sodium retention in the CKD population can lead to hypertension, edema, and progressive disease. Sodium excess is responsible for increases in oxidative stress, which alters kidney vasculature. As progression of CKD occurs, hyperfiltration by remaining nephrons compensates for an overall decrease in the filtered load of sodium. In the later stages of CKD, compensatory mechanisms are overcome and volume overload ensues. Nephrotic syndrome as it relates to sodium handling involves a different pathophysiology despite a common phenotype. Extrarenal sodium buffering is also examined as it has significant implications in the setting of advanced CKD.

Topics: Animals; Atrial Natriuretic Factor; Diet, Sodium-Restricted; Homeostasis; Humans; Hypertension; Nephrotic Syndrome; Oxidative Stress; Renal Insufficiency, Chronic; Renin-Angiotensin System; Skin; Sodium; Sympathetic Nervous System; Vasopressins

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Humans; Kidney Failure, Chronic; Nephrotic Syndrome; Prognosis; Renal Dialysis; Renin-Angiotensin System

Resistance to the natriuretic action of atrial natriuretic peptide (ANP) is a hallmark of states of pathological sodium retention including congestive heart failure, cirrhosis of the liver, and nephrotic syndrome. A variety of mechanisms including reduced delivery of filtrate to ANP-sensitive sites in the inner medullary collecting duct and diminished receptor density in this tubular segment have been offered to account for this resistance. Recent studies in experimental nephrotic syndrome and in liver disease produced by ligation of the common bile duct in rats suggest that increased activity of cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase may be an important mediator of renal resistance to ANP. Such increased enzyme activity rapidly catabolizes the second messenger cGMP, normally formed when ANP interacts with its biologically active natriuretic peptide A receptors, thereby leading to blunted ANP responsiveness. This increased phosphodiesterase activity offers a novel approach to the management of clinical conditions associated with sodium retention and edema formation.

Topics: Animals; Atrial Natriuretic Factor; Drug Resistance; Heart Failure; Humans; Kidney; Liver Cirrhosis, Experimental; Nephrotic Syndrome; Phosphoric Diester Hydrolases; Sodium Chloride

In the nephrotic syndrome abnormal sodium and water retention occurs at the kidney level that ultimately causes expansion of interstitial volume and edema. The mechanisms and factors involved remain ill defined. The traditional view has considered hypovolemia, due to urinary protein losses and decreased oncotic pressure, as the afferent stimulus of a complex pathway of responses that come together to enhance reabsorption of sodium and water along the nephron. However, given the fact that only a minority of nephrotic patients have low plasma volume, it has been hypothesized that sodium retention by the kidney is a primary phenomenon occurring in response to intrarenal rather than systemic mechanisms. Experimental evidence is available to support this possibility, and indicates that distal nephron sites are involved in avid sodium retention in the nephrotic syndrome. Several studies have been designed to establish the role of neurohumoral mediators, including the renin-angiotensin-aldosterone axis and sympathetic nervous system. These data suggest that although activation of these systems may contribute to salt retention, they may be minor factors in this process. Recently, attention has focused on atrial natriuretic peptides (ANP), which increase sodium and water excretion in experimental animals and humans. A markedly blunted natriuretic and diuretic response to the systemic infusion of ANP has been reported in the nephrotic syndrome. A defect in the number and affinity of receptor binding sites for the peptide as well as in the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP, has recently been investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Edema; Humans; Nephrons; Nephrotic Syndrome; Sodium

The nephrotic syndrome is associated with an expanded interstitial volume and edema due to sodium and water retention. The mechanisms underlying these abnormalities have been only partially clarified. Renal hypoperfusion has been considered the key event that promotes avid sodium and water reabsorption by the kidney. Hypoperfusion results from hypovolemia, a consequence of urinary protein losses and decreased oncotic pressure. However, in some patients plasma volume is normal or even increased, suggesting that in such cases the cause of sodium and water retention might be independent of systemic events and possibly originates in the kidney. Experimental evidence is now available to support this, but the intrarenal mediator(s) that promote the abnormal salt retention are still not fully clear. Atrial natriuretic peptide (ANP), which increases sodium and water excretion, has been suspected to participate in fluid retention. This is consistent with experimental and human data of a markedly blunted natriuretic and diuretic response to systemic infusion of ANP in the nephrotic syndrome. Recent studies of the mechanisms of the blunted natriuretic and diuretic response to ANP documented an increased activity of renal sympathetic nerves, but the results are controversial. The altered response to ANP also may be related to a defect in the number and affinity of receptor-binding sites for the peptide. Evidence also is available of a possible defect at the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP. The gene encoding for a cyclophilin-like protein, which is increased in sodium-retaining conditions, is upregulated in the kidneys of nephrotic rats, and the infusion of ANP further increases cyclophilin-like protein mRNA. Thus, multiple factors probably act in concert to induce edema formation in the nephrotic syndrome. In this review we specifically address the tubular insensitivity to the natriuretic and diuretic action of ANP, which could be an important initiating event and could possibly contribute to sustaining the edema.

Topics: Animals; Atrial Natriuretic Factor; Edema; Humans; Natriuresis; Nephrotic Syndrome

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Edema; Humans; Kidney; Nephrotic Syndrome; Rats; Sodium

This article provides a brief overview of atrial natriuretic factor (ANF). Considered by many investigators to be the putative "third factor" governing sodium excretion, ANF is a peptide actively secreted by the heart, with multiple target organ effectors. As such, ANF represents the first clearly documented cardiac hormone.

Topics: Animals; Atrial Natriuretic Factor; Edema; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Nephrotic Syndrome

To compare the diuretic effect of coadministration of dextran and flurosemide with that of coadministration of Albumin and flurosemide on primary nephrotic syndrome.. In a double-blind placebo-controlled study, eighteen primary nephrotic syndrome patients on standard sodium chloride intake, random by divided into three groups and received by intravenous administration for 60 minutes for three days (a) FU (1 mg.kg-1) combination with a sham infusion, (b) FU (1 mg.kg-1) combination with 50 ml of 20% solution of Albumin, or (c) FU (1 mg/kg) combination with 250 ml dextran 40. Urinary volume, sodium and plasma atrial nartiuretic peptide concentration were assessed.. The results showed that administration of FU alone increased mean cumulative urinary sodium and volume excretion as compared with the administration of sham infusion without treatment (P < 0.05). The administration of FU and albumin or FU and dextran 40 caused an even more marked increase of urinary sodium and volume excretion (P < 0.01), as compared with the administration of sham infusion without treatment. Plasma ANP increased significantly on both albumin infusion days and dextran 40 infusion days (P < 0.05).. Coadministration of albumin and FU or dextran 40 and FU can increase the urinary volume and urinary Na and ANP significantly, dextran 40 can take the place of albumin because there was no difference between the administration of FU and albumin and FU and dextran in UV, Una and ANP.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Dextrans; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Furosemide; Humans; Male; Middle Aged; Nephrotic Syndrome; Plasma Substitutes

It is well known that posture affects natriuresis in cirrhosis and heart failure. This study evaluates the role of posture on spontaneous urinary salt excretion (U(Na)V) and diuretic-induced natriuresis in nephrotic patients with mild renal impairment. U(Na)V and plasma concentrations of the main hormones involved in sodium regulation were evaluated at baseline (Baseline) and after furosemide administration (20 mg intravenously at 8:00 AM [Diuretic]) in seven nephrotic patients with mild renal impairment (creatinine clearance, 68.5 +/- 7.6 mL/min) in either the supine or upright position for 6 hours (from 8:00 AM to 2:00 PM). At baseline, U(Na)V was greater in the supine than upright position (sodium, 51.8 +/- 6.2 versus 38.3 +/- 6.1 mEq/d; P: < 0.01). Similarly, furosemide was more effective in increasing U(Na)V in the supine (sodium, 51.8 +/- 6.2 to 87.4 +/- 9.1 mEq/d; P: < 0.005) than upright position (sodium, 38.3 +/- 6.1 to 59.0 +/- 6.8 mEq/d; P: = not significant). Consequently, body weight decreased in the supine but not the upright position (-0.73 +/- 0.15 versus -0.17 +/- 0.22 kg; P: < 0. 05). Peripheral renin activity (PRA) and plasma aldosterone (Aldo) concentrations were greater in the upright than supine position at both Baseline and Diuretic. A similar pattern was observed for hematocrit, used as an index of plasma volume. In addition, a positive correlation was detected between hematocrit and PRA (r = 0.89; P: < 0.001) in the upright position. Postural changes did not influence plasma concentrations of atrial natriuretic peptide. These data indicate that in nephrotic patients with mild impairment of glomerular filtration rate, the upright position causes a reduction in plasma volume; this hypovolemia activates the renin-Aldo system responsible for sodium retention in unstimulated conditions and a blunted natriuretic response to furosemide.

Topics: Aldosterone; Atrial Natriuretic Factor; Diuretics; Female; Furosemide; Hematocrit; Humans; Kidney Function Tests; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Plasma Volume; Renin; Single-Blind Method; Sodium

In patients with nephrotic syndrome, the natriuretic effect of furosemide (FU) is diminished. The effect of coadministration of FU and human albumin (HA) has remained controversial.. In a double-blind, placebo-controlled study, nine nephrotic patients (six males, 48 +/- 4 years) on standardized sodium chloride intake, in random order on three separate days, received by intravenous administration for 60 minutes either (a) 60 mg FU plus a sham infusion, (b) 60 mg FU plus 200 ml of a 20% solution of HA, or (c) sham infusion plus 200 ml of a 20% solution of HA. Urinary volume, sodium, albumin and FU excretion, renal hemodynamics, and plasma atrial natriuretic factor concentration were assessed.. Administration of FU alone significantly (P < 0.01) increased mean cumulative urinary sodium (259 +/- 30 mmol) and volume excretion (2684 +/- 167 ml) in the first eight hours as compared with the HA infusion alone (118 +/- 12 mmol, 1827 +/- 141 ml). The coadministration of FU and HA caused an even more marked increase (P < 0.01 vs. HA alone) of urinary sodium (312 +/- 28 mmol) and volume excretion (3230 +/- 201 ml); the difference to FU administration alone was significant (P < 0.05). Plasma atrial natriuretic factor, serum albumin concentration, and urinary albumin excretion increased significantly on both HA infusion days, whereas urinary excretion of FU remained unchanged with HA coadministration. Glomerular filtration rate (CIn) was not significantly affected by any of the infusion protocols, but effective renal plasma flow (CPAH) increased significantly on both HA infusion days.. Coadministration of HA potentiates the action of FU in patients with the nephrotic syndrome, but only modestly. This effect is mediated by changes in renal hemodynamics.

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Cross-Over Studies; Diuresis; Double-Blind Method; Drug Combinations; Drug Synergism; Female; Furosemide; Humans; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Renal Circulation; Serum Albumin

Oedema formation in the nephrotic syndrome is primarily due to tubular sodium retention. The pathogenetic role of alpha atrial natriuretic peptide (ANP), a hormonal promoter of natriuresis is unknown.. In 31 patients (aged 35+/-11 years) with nephrotic syndrome and histopathological evidence of primary glomerulonephritis, we investigated plasma ANP concentration and its influence on renal haemodynamics, natriuresis, and proteinuria (total protein, albumin, IgG excretion). Patients with a compensated treated form of nephrotic syndrome due to primary glomerulonephritis were included in the study. Serum creatinine levels were <=1.4 mg/dl. Diuretic medication was discontinued at least 24 h before the investigation was started. Patients were randomly assigned to ANP infusion (0.005 microg/kg*min; group II, n=15) or received placebo (group III, n=16). Ten healthy subjects (group I) served as normal controls.. In normal subjects (group I), ANP caused an increase in natriuresis from 14.5+/-4.2 mmol/h to 26.4+/-11.1 mmol/h (P<0.01). In patients with nephrotic syndrome (group II), baseline sodium excretion of 10.5+/-6.0 mmol/h was increased to 19.6+/-14.8 mmol/h with ANP infusion (P<0.01). No changes were seen in the placebo group III. The absolute increase in ANP induced natriuresis was not significantly different between group I and II. However, plasma ANP levels were significantly higher in patients with nephrotic syndrome (166+/-87 pg/ml vs. 74+/-21 pg/ml, P<0.05) and also reached higher levels after ANP infusion (P<0.01). Therefore, natriuresis was significantly reduced when circulating ANP levels were taken into account (P<0.05). ANP administration resulted in an increase of total protein excretion in patients with the nephrotic syndrome (group II, from 219+/-277 mg/h to 264+/-268 mg/h). Albumin elimination rose from 128+/-151 mg/h to 167+/-170 mg/h (P<0.05) and IgG excretion from 4.91+/-6.67 mg/h to 9.27+/-10.78 mg/h (P<0.05). Healthy subjects also showed a small but significant increase in albuminuria (48+/-38%, P<0.05). Low-dose ANP infusion did not, however, induce any significant alteration in GFR, ERPF and blood pressure.. ANP plasma concentrations in the steady state are elevated in patients with the nephrotic syndrome. The natriuretic effect of ANP is reduced when referring to circulating ANP plasma levels. Elevated ANP levels enhance urinary protein excretion in the nephrotic syndrome. This is not due to modulation of GFR or FF, but is most probably attributable to increased glomerular permeability.

Topics: Adult; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Female; Hemodynamics; Humans; Male; Natriuresis; Nephrotic Syndrome; Proteinuria; Renal Circulation; Serum Albumin; Sodium

The exact role of atrial natriutetic peptide (ANP) in the pathogenesis of edema in nephrotic syndrome (NS) has not been fully elucidated. We aimed to investigate the possible contribution of ANP to edema formation in NS.. We subjected 18 nephrotic subjects and 20 healthy volunteers to supine bicycle exercise (SBE), a maneuver that seemed to increase venous return and to enhance the release of ANP. Plasma concentrations of immunoreactive-ANP were measured before and after SBE by radioimmunoassay.. There was a significant rise in the plasma concentration of ANP in the controls after SBE (from 31.1 +/- 6.16 to 42.0 +/- 6.01 pg/ml: p < 0.05). Meanwhile, there was no change in plasma concentration of ANP in the patients with NS (from 35.4 +/- 6.04 to 35.1 +/- 5.31 pg/ml). The change in plasma concentration of ANP in controls was significantly different from that in those with NS (p < 0.05). The mean baseline value of ANP in controls was the same as in NS.. These results show that SBE was a simple maneuver to stimulate the release of ANP in healthy controls. In contrast, it failed to stimulate the release of ANP in subjects with NS.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Exercise; Female; Humans; Male; Middle Aged; Nephrotic Syndrome; Radioimmunoassay; Supine Position; Venous Insufficiency

Because the role of systemic hormones in the pathophysiology of edema in acute renal disease remains incompletely understood, we compared the levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA) in patients with acute glomerulonephritis (AGN), nephrotic syndrome (NS), and normal individuals during salt deprivation and salt loading. Sixteen patients with AGN (10 males) and nine patients with NS and hypoalbuminemia (7 males) were studied on admission, and after recovery (12 AGN patients) or remission (4 NS patients). Eighteen normal controls were each studied after five days on a low (20 mEq Na/day), regular (120 mEq Na/day) and high (300 mEq Na/day) dietary salt intake. Patients with AGN and NS had comparable edema (AGN 2.8 +/- 0.53 kg; NS 3.36 +/- 0.47 kg; SE) and urinary Na excretion (mean +/- SEM: AGN 0.97 +/- 0.11 mEq/hr; NS 1.06 +/- 0.16 mEq/hr), but AGN patients had five times higher ANF (AGN 27.2 +/- 4.06 fmol/ml; NS 5.51 +/- 1.02 fmol/ml; P less than 0.001) and six times lower PRA ng/liter.sec levels (AGN 0.187 +/- 0.047; NS 1.144 +/- 0.222; P less than 0.001) than NS patients. The degree of edema was correlated with ANF levels in AGN patients (P less than 0.001) but not in NS patients. There was a strong exponential negative correlation (r = -0.773, P less than 0.0001) between ANF and PRA, in which AGN patients and Na-restricted controls were located in the opposite ends of the volume sensing-response, and NS patients in the middle, alongside controls with regular Na intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Atrial Natriuretic Factor; Child; Diet, Sodium-Restricted; Edema; Female; Glomerulonephritis; Humans; Male; Natriuresis; Nephrotic Syndrome; Renin; Sodium, Dietary

The diuretic and natriuretic responses to exogenous synthetic atrial natriuretic peptide (ANP) were evaluated in patients with chronic renal failure (CRF) or nephrotic syndrome (NS). Patients were studied after an oral water load (8 ml/kg in CRF and 20 ml/kg in NS patients). A short intravenous bolus of either a placebo or ANP was administered when urine output was stable. In each group of patients, three doses of ANP were injected at 24 h intervals, i.e., 1.0, 1.5, and 2.0 micrograms/kg in the CRF and 1.0, 1.5, and 3.0 micrograms/kg in the NS group. Blood pressure and heart rate were monitored throughout the study and urinary volume and electrolyte excretion were measured every 20 min up to 3 h after the bolus. An acute and transient fall in blood pressure was observed immediately after the ANP injection. It was more pronounced in CRF than in NS patients. In CRF patients, ANP caused only a slight increase in urinary volume (13.5-44% over baseline) but a significant increase in urinary sodium excretion (45-114% over baseline). In NS patients, significant increases in both urine volume (60-105%) and sodium excretion (149-248%) were also found. In these latter patients, the renal response to ANP appeared to be better preserved. The hemodynamic and renal changes induced by ANP occurred mainly during the first 20 min following the ANP administration, when the peak plasma ANP levels were obtained. However, no clear dose-response effect could be evidenced in either group with the three doses of ANP chosen in this study.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Hormones; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Nephrotic Syndrome; Sodium

Synthetic human ANP (102-126) or vehicle was intravenously administered to eight patients with non-edematous nephrotic syndrome to study its effect on protein and sodium excretion. ANP was given in ascending doses, each dose for one hour, two to three days apart. Four patients received 0.03, 0.10 and 0.45 microgram/kg/min of ANP, and four received 0.015, 0.06 and 0.20 microgram/kg/min. Natriuresis increased at all doses; by 179 +/- 13.6% (mean +/- SEM; P less than 0.05) at 0.015 microgram/kg/min and by 660 +/- 71.5% (P less than 0.01) at 0.20 microgram/kg/min. Urinary albumin excretion increased by 138 +/- 30.1% (P less than 0.05) at 0.015 microgram/kg/min of ANP and by 534 +/- 132% (P less than 0.01) at 0.20 microgram/kg/min. Immunoglobulin G excretion increased proportionally to albumin excretion. Hematocrit and serum albumin concentration increased after ANP. In each patient the percent reduction of plasma volume calculated from the effect on serum albumin was smaller than the hemoconcentration calculated from the effect on hematocrit, suggesting a loss of albumin from the intravascular compartment. This could not be accounted for by the increased glomerular filtration of albumin. Blood pressure and effective renal plasma flow decreased and filtration fraction increased after ANP. Plasma renin was suppressed at lower doses of ANP but was stimulated, together with plasma noradrenaline, at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Diuretics; Hormones; Humans; Immunoglobulin G; Male; Natriuresis; Nephrotic Syndrome; Peptide Fragments

This study aimed to evaluate available volume status assessment tools in nephrotic syndrome (NS). Sixty children with INS were subdivided into hypovolemic and nonhypovolemic groups based on fractional excretion of sodium (FeNa%); all were studied for inferior vena cava collapsibility index (IVCCI), plasma atrial natriuretic peptide (ANP), and body composition monitor (BCM). Forty-four patients had nonhypovolemic and 16 had hypovolemic states. ANP did not differ between both groups. IVCCI was higher in hypovolemic group (p < 0.001) with sensitivity 87.5% and specificity 81.8% for hypovolemia detection, while BCM overhydration (BCM-OH) values were higher in nonhypovolemic group (p = 0.04) with sensitivity = 68.2% and specificity = 75% for detection of hypervolemia. FeNa% showed negative correlation with IVCCI (r =  -0.578, p < 0.001) and positive correlation with BCM-OH (r = 0.33, p = 0.018), while FeNa% showed nonsignificant correlation to ANP concentration. IVCCI is a reliable tool for evaluating volume status in NS and is superior to BCM.

Topics: Atrial Natriuretic Factor; Child; Edema; Humans; Hypovolemia; Nephrotic Syndrome; Sodium; Ultrasonography; Vena Cava, Inferior

The acute onset of idiopathic nephrotic syndrome (NS) is often accompanied by acute kidney injury, which can lead to congestive heart failure and lung edema. In this report, we present two cases of NS-induced acute kidney injury successfully treated with a low dose of carperitide, a human atrial natriuretic peptide. In combination with standard diuretic therapy and immunotherapy, carperitide retained the renal function and spared the need for renal replacement therapy, including hemodialysis. Although further investigation in clinical trials is required to validate these findings, carperitide may be useful for maintaining the renal function in cases of NS-induced acute kidney injury.

Topics: Acute Kidney Injury; Aged, 80 and over; Atrial Natriuretic Factor; Female; Humans; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome

The edema formation in nephrotic syndrome (NS) is associated with a blunted response to atrial natriuretic peptide (ANP). The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R). We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS). Urinary sodium, cyclic guanosine monophosphate (cGMP) excretion, and D1R protein expression and localization in renal tubules were evaluated in PAN-NS and control rats before and during volume expansion (VE). The effects of zaprinast (phosphodiesterase type 5 inhibitor), alone or in combination with Sch-23390 (D1R antagonist), were examined in both groups. The increased natriuresis and urinary cGMP excretion evoked by acute VE were blunted in PAN-NS despite increased levels of circulating ANP. This was accompanied in PAN-NS by a marked decrease of D1R expression in the renal tubules. Infusion of zaprinast in PAN-NS resulted in increased urinary excretion of cGMP and sodium to similar levels of control rats and increased expression of D1R in the plasma membrane of renal tubular cells. Combined administration of Sch-23390 and zaprinast prevented natriuresis and increased cGMP excretion induced by zaprinast alone. We conclude that D1R may play a major role in the ANP resistance observed in PAN-NS.

Topics: Animals; Atrial Natriuretic Factor; Benzazepines; Cyclic GMP; Glomerular Filtration Rate; Homeostasis; Kidney; Male; Natriuresis; Nephrotic Syndrome; Purinones; Puromycin Aminonucleoside; Rats; Receptors, Dopamine D1; Sodium

The natriuretic/diuretic response to atrial natriuretic peptide (ANP), an important regulator of water and Na(+) balance, is markedly attenuated in nephrotic syndrome (NS). It has been suggested that the diminished renal responsiveness to ANP may contribute to the pathogenesis of salt retention and edema formation in NS. However, the mechanisms underlying the renal hyporesponsiveness to ANP remain largely unknown.. The acute effects of exogenous infusion of ANP (5 µg/kg + 10 µg/kg/h) were studied by clearance methodology in control rats, hypoalbuminemic rats with Adriamycin (ADR)-induced NS and in ADR-treated rats infused with hyperoncotic albumin sufficient to restore plasma albumin to normal levels.. Administration of ANP to control rats resulted in a significant increase in urinary flow rate, absolute rate of sodium excretion (+456%) and glomerular filtration rate (GFR). Mean arterial blood pressure decreased following infusion of the peptide. In the nephrotic rats, baseline GFR and Na(+) excretion were significantly lower than in the control animals, and the renal effects of ANP were markedly blunt compared to the control animals. In contrast, the hypotensive effect of ANP in the ADR-treated rats was largely preserved. Infusion of hyperoncotic albumin prior to ANP administration reversed the decrease in baseline GFR and Na(+) excretion and completely restored the renal effects of ANP in the nephrotic rats.. These findings indicate that renal hyporesponsiveness to ANP in rats with ADR-induced NS is a reversible phenomenon that appears to be of functional origin rather than reflecting permanent cellular damage.

Topics: Albumins; Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Doxorubicin; Edema; Glomerular Filtration Rate; Humans; Hypotension; Inulin; Kidney; Male; Natriuresis; Nephrosis; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; Salts; Sodium

The pathogenesis of edema in nephrotic syndrome is not entirely understood. The aim of this study was to contribute to the discussion on edema pathogenesis in nephrotic syndrome by following changes in volume and sodium retention for the course of the disease in children with steroid-sensitive nephrotic syndrome (SSNS).. Forty-one children with SSNS were included in the study. The patients were divided into three groups (group I: relapse-edematous; group II: relapse-edema free; group III: remission). We investigated the value of the significance and area of sodium retention and vasoactive hormones. In addition, we measured parameters such as inferior vena cava collapsibility index, left atrium diameter, and total body water (TBW) to determine the volume load and cause of edema in children with SSNS.. TBW increased in the relapse-nephrotic syndrome group and the difference was statistically significant among groups (P < 0.001). However, inferior vena cava collapsibility index and left atrium diameter were not different among groups. Fractional sodium excretion was lower in children with relapse nephrotic syndrome (P < 0.05).. Although TBW increases in children with SSNS, intravascular volume is normal. In addition, hypoalbuminemia and sodium retention of the proximal tubule cause edema in children with SSNS.

Topics: Albumins; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Body Water; Child; Child, Preschool; Echocardiography, Doppler, Color; Edema; Female; Heart Atria; Humans; Male; Nephrotic Syndrome; Recurrence; Renin; Sodium; Vena Cava, Inferior

Patients with proteinuric kidney diseases often have symptoms of salt and water retention. It has been hypothesized that dysregulated sodium absorption is due to increased proteolytic cleavage of epithelial sodium channels (ENaCs) and increased Na,K-ATPase expression. Microarray analysis identified a reduction in kidney corin mRNA expression in rat models of puromycin aminonucleoside-induced nephrotic syndrome and acute anti-Thy1 glomerulonephritis (GN). As atrial natriuretic peptide (ANP) resistance is a mechanism accounting for volume retention, we analyzed the renal expression and function of corin; a type II transmembrane serine protease that converts pro-ANP to active ANP. Immunohistochemical analysis found that corin colocalized with ANP. The nephrotic and glomerulonephritic models exhibited concomitant increased pro-ANP and decreased ANP protein levels in the kidney consistent with low amounts of corin. Importantly, kidneys from corin knockout mice had increased amounts of renal β-ENaC and its activators, phosphodiesterase (PDE) 5 and protein kinase G II, when compared to wild-type mice. A similar expression profile was also found in cell culture suggesting the increase in PDE5 and kinase G II could account for the increase in β-ENaC seen in nephrotic syndrome and GN. Thus, we suggest that corin might be involved in the salt retention seen in glomerular diseases.

Topics: Animals; Aquaporin 2; Atrial Natriuretic Factor; Cyclic AMP; Epithelial Sodium Channels; Glomerulonephritis; HEK293 Cells; Humans; Kidney; Male; Mice; Nephrotic Syndrome; Proteinuria; Rats; Rats, Wistar; Serine Endopeptidases; Sodium

The serine/threonine protease corin, which proteolytically activates atrial natriuretic peptide (ANP), is reduced in the kidneys of animals with nephrotic syndrome and glomerular nephritis. Polzin et al. provide evidence for a linkage between the decreased corin and β-epithelial sodium channel, phosphodiesterase 5, and cGMP-dependent protein kinase II in the nephrotic kidney. They propose that decreases in cGMP resulting from the reduced corin may be responsible for the Na(+) retention and volume expansion that are hallmarks of these kidney diseases.

Topics: Absorption; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Nephrotic Syndrome; Serine Endopeptidases; Sodium

Topics: Adult; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Nephrotic Syndrome; Treatment Outcome

Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive uroguanylin (ir-uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-uroguanylin and sodium peaked, the plasma level of ir-uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of uroguanylin, these results suggested that uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Biomarkers; Disease Models, Animal; Male; Molecular Sequence Data; Natriuresis; Natriuretic Peptides; Nephrotic Syndrome; Peptides; Probability; Puromycin Aminonucleoside; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Nephrotic syndrome is characterized by severe proteinuria and sodium and water retention. Although endothelin (ET) 1 can cause natriuresis or antinatriuresis, the role played by ET-1 in proteinuria and in sodium retention due to nephrotic syndrome remains unclear.. We investigated the role played by the ET-1 system in sodium and water retention and in proteinuria in puromycin aminonucleoside induced nephrotic syndrome in rats using microdissected nephron segments, competitive polymerase chain reaction, and Western blot.. The expression of prepro ET-1, ET-converting enzyme 1 (ECE-1), and ET A receptor mRNAs, but not ET B receptor mRNA, in the glomeruli was increased in rats with nephrotic syndrome. The cGMP generation in the glomeruli induced by atrial natriuretic peptide and ET-1 was decreased, whereas the ET-3-induced cGMP generation was increased in rats with nephrotic syndrome. ECE-1 mRNA expression was increased not only in the glomeruli, but also in the thick ascending limbs and collecting ducts. The protein expression of ECE-1 was increased in the membrane fraction of the cortex and in the outer and the inner medulla of nephrotic rats. Blockade of ET A and B receptors by bosentan did not inhibit the occurrence of nephrotic syndrome. However, the administration of bosentan increased the urinary sodium excretion.. These data suggest that an activated ET-1-ET A receptor pathway in glomeruli and/or an increased ECE-1 mRNA expression in distal segments may participate in sodium and water retention, but not in the occurrence of nephrotic syndrome.

Topics: Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Bosentan; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Enzyme Induction; Gene Expression Regulation, Enzymologic; Kidney Glomerulus; Male; Metalloendopeptidases; Nephrons; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Time Factors

The resemblance of the circadian rhythm of glomerular filtration rate (GFR) to that of arterial blood pressure (BP) suggests that systemic hemodynamic factors contribute to this variation. In the present study, this was investigated using continuous BP monitoring and pulse wave analysis. The study was performed in eight healthy subjects and in seven patients with nephrotic syndrome who had normal or reversed rhythms of GFR.. Circadian variations of renal function (continuous infusion of inulin/paraaminohippuric acid), noninvasive finger arterial pressure (Portapres), and vasoactive hormone levels were monitored during 27 hours. With stepwise backward regression analysis, the contributions of the measured variables to the circadian variation of GFR were investigated.. Both groups showed a reduction of BP at night. In the controls, this was related to a drop in cardiac output, while in the patients, total peripheral resistance decreased at night. None of the hemodynamic variables explained the circadian GFR variation in both groups. In the controls, only 6% of the effective renal plasma flow (ERPF) rhythm was associated with variations in cardiac output (P = 0.03). In the patients, atrial natriuretic peptide and plasma renin activity were responsible for 36% of the variation in GFR (P < 0.01).. These results indicate that the circadian variation of GFR does not result directly from changes in BP or cardiac output. An inverted GFR rhythm in patients with nephrotic syndrome may originate from hormonal mechanisms rather than directly from the hemodynamic effects of edema mobilization.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Case-Control Studies; Circadian Rhythm; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Renal Circulation; Renin

Topics: Age Factors; Aged; Amyloidosis; Animals; Atrial Natriuretic Factor; Back Pain; Diagnosis, Differential; Doxorubicin; Dyspnea; Echocardiography; Electrocardiography; Fish Oils; Glomerulonephritis; Histocytochemistry; Humans; Kidney; Male; Microscopy, Electron; Nephrotic Syndrome; Rats

Uroguanylin, a new natriuretic peptide originally isolated from urine, stimulates the membrane guanylate cyclase C receptor. No information, however, is available on the plasma and urine levels of uroguanylin in nephrotic syndrome (NS), the state associated with sodium and water retention. Using a sensitive radioimmunoassay, we measured the plasma and urine concentrations of immunoreactive (ir-)uroguanylin in NS patients and compared them with those of patients with non-nephrotic glomerulonephritis. Plasma ir-uroguanylin, blood pressure and the cardiothoracic ratio were higher, and urine excretion of ir-uroguanylin was lower in the NS patients. Plasma ir-uroguanylin in the NS patients significantly decreased during remission as compared with findings on admission. There was a significant inverse correlation between the concentration of plasma ir-uroguanylin and that of serum total protein or albumin. Moreover, fluid retention in the NS patients was correlated with the changes in plasma ir-uroguanylin between admission and remission, indicative that the plasma concentration increases with the severity of the nephrotic state. Taking into account its potent natriuretic effect, these findings suggest that uroguanylin may function in the pathophysiological mechanism in NS.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Glomerulonephritis; Guanylate Cyclase; Humans; Kidney; Male; Natriuretic Peptides; Nephrotic Syndrome; Peptides; Serum Albumin

Nephrotic syndrome is associated with resistance to the renal actions of atrial natriuretic peptide (ANP). We performed experiments in anesthetized, acutely nephrectomized rats 21-28 days after injection of adriamycin (7-8 mg/kg i.v.) or 9-14 days after injection of anti-Fx1A antiserum (5 ml/kg i.p.) (passive Heymann nephritis; PHN) to test whether extrarenal resistance also occurred. Proteinuria was significantly elevated in both models compared with controls before study. ANP infusion (1 microgram.kg-1.min-1) caused arterial pressure to decrease similarly in control rats, adriamycin-treated rats, and rats with PHN (by 8.2 +/- 1.0, 9.4 +/- 2.3, and 9.0 +/- 2.0%, respectively; all P < 0.05 vs. both baseline and vehicle-infused control rats). In control rats, hematocrit increased progressively to a maximal value 9.5 +/- 0.9% over baseline as a result of the infusion, an increase corresponding to a reduction in plasma volume of 16.1 +/- 0.9%. The ANP-induced increase in hematocrit was preserved in adriamycin-treated rats (9.2 +/- 1.3%) but was markedly blunted in rats with PHN (2.4 +/- 1.3%; P < 0.0001 vs. ANP infusion in control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate was significantly lower in rats with PHN compared with both control and adriamycin-treated rats. Infusion of a subpressor dose of angiotensin II (ANG II, 2.5 ng.kg-1.min-1) fully restored the ANP-induced increase in hematocrit in rats with PHN. This study demonstrates that 1) the hemoconcentrating and hypotensive actions of ANP are preserved in adriamycin-treated rats, 2) the effect of ANP on hematocrit and fluid distribution is blunted in rats with PHN while its hypotensive action is preserved, and 3) low-level ANG II infusion normalizes the hemoconcentrating effect of exogenously infused ANP in rats with PHN. Thus deficient ANG II generation in rats with PHN, but not adriamycin nephrosis, may contribute to extrarenal ANP resistance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Proteins; Blood Volume; Cyclic GMP; Doxorubicin; Glomerulonephritis; Hematocrit; Hemodynamics; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

Haplotype analysis and alpha-fetoprotein quantitation comprise a prenatal diagnosis of congenital nephrosis. Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease characterized by massive proteinuria and nephrotic syndrome from birth. Prenatal diagnosis of CNF has previously been based on the quantitation of alpha-fetoprotein (AFP) in the amniotic fluid and maternal serum, but an increased AFP is not specific for the disease. We have recently localized the CNF gene to the chromosome 19q13.1 region and observed a strong linkage disequilibrium to the genetic markers D19S610, D19S608, D19S224 and D19S220 in this chromosomal area. Four main CNF-haplotypes have been observed in Finnish kindreds. In the present study, linkage and haplotype analyses have been applied to prenatal diagnosis of six families with a history of CNF. The results diminish the risk of false positive diagnosis and abortions of healthy fetuses in families at risk.

Topics: Amniotic Fluid; Atrial Natriuretic Factor; Chromosomes, Human, Pair 19; DNA Mutational Analysis; Evaluation Studies as Topic; Female; Finland; Genes, Recessive; Genetic Markers; Haplotypes; Humans; Linkage Disequilibrium; Male; Nephrotic Syndrome; Pedigree; Pregnancy; Prenatal Diagnosis; Risk Factors

Topics: Adolescent; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Child; Child, Preschool; Disease Progression; Edema; Humans; Kidney Function Tests; Nephrotic Syndrome; Osmotic Pressure; Remission, Spontaneous; Renin; Serum Albumin; Sodium

Topics: Atrial Natriuretic Factor; Case-Control Studies; Child; Female; Humans; Male; Nephrotic Syndrome

Renin-angiotensin-aldosterone system, plasma atrial natriuretic peptide (PANP), and blood volume (BV) have been investigated in 20 nephrotic patients with normal renal function and with (group 1; n = 12) or without (group 2; n = 8) sodium retention. Patients of group 1 had a plasma albumin (PALB) concentration < 1.7 g/dl, low BV and PANP levels, a reduced fractional excretion of lithium (FELi), and high plasma angiotensin II levels. Patients of group 2 had PALB > 1.7 g/dl, and the other parameters were normal. The spontaneous intake of dietary sodium was lower in group 1 than in group 2. In all patients the BV was directly correlated with PALB, and the plasma renin activity (PRA) was inversely correlated with both BV and PALB. A nonlinear inverse relationship was present between plasma aldosterone (PALD) levels and fractional excretion of sodium (FENa). The acute expansion of the BV in patients of group 1 normalized PRA, PALD, PAII, FENa, and FELi and increased PANP. The administration of spironolactone to the patients of both groups had variable effects on FENa, did not modify PRA and PALD, and reduced body weight, PANP, and FELi, thus suggesting that the reduction of BV induced by the drug increased the proximal reabsorption of sodium. Three additional patients who had sodium retention, PALB of 2.3-2.4 g/dl, normal PRA and PALD, elevated urinary excretion of aldosterone, and a slightly low PANP showed a spontaneous normalization of urinary aldosterone and PANP associated with natriuresis and weight loss, but thereafter urinary aldosterone increased, PANP decreased, and the sodium retention began again. Our data suggest that in nephrotic patients with severe hypoalbuminemia, contraction of BV plays a major role in promoting the sodium retention through the activation of compensatory hormonal mechanisms. On the other hand, when PALB is not severely reduced, the patients have normal BV, but they are very sensitive to small changes of BV which are better evidenced by modifications of the urinary excretion of aldosterone and PANP rather than by the profiles of PRA and PALD.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Volume; Diuretics; Humans; Kidney; Lithium; Middle Aged; Nephrotic Syndrome; Peptide Fragments; Renin-Angiotensin System; Serum Albumin; Sodium; Sodium, Dietary; Spironolactone

To evaluate therapeutic and side effects, atrial natriuretic peptide (ANP) was administered as a pharmacological bolus dose (2 micrograms/kg body weight) to 7 patients with nephrotic syndrome and to 13 age- and gender-matched control subjects. The basal glomerular filtration rate was similar, but the blood pressure was slightly higher in the patients than in the controls. Injection of ANP induced a significant increase of sodium excretion in controls (from 0.21 to 0.52 mmol/min, medians, p < 0.01), but not in nephrotics (from 0.21 to 0.32 mmol/min). Urinary output and free water clearance after ANP had been given were also lower in the patients. The natriuretic effect was mediated through inhibition of distal tubular fractional sodium reabsorption, as estimated by the lithium clearance technique, and through an increase of glomerular filtration rate, both effects only significant in the healthy subjects. The blood pressure was reduced to the same extent in the two groups. Although similar levels of ANP were reached in the groups after injection, cyclic guanosine monophosphate (GMP)/ANP was less in the patients, both basally and after ANP injection, and the urinary excretion of cyclic GMP did not increase in the nephrotics (from 478 to 1,220 pmol/min, ns) as in the controls (from 389 to 2,500 pmol/min, p < 0.01). The urinary albumin excretion rate increased significantly in patients, whereas the prostaglandin E2 excretion increased after ANP administration only in controls. Endothelin, angiotensin II, aldosterone, and arginine vasopressin were unchanged in the two groups. Basal aldosterone was lower and ANP higher in patients than in controls. In conclusion, the natriuretic effect of ANP was reduced in nephrotic patients. This could not be attributed to counterregulatory haemodynamic or hormonal factors, but probably to reduced second messenger cyclic GMP.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Body Water; Case-Control Studies; Cyclic GMP; Dinoprostone; Endothelins; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Nephrotic Syndrome; Renal Plasma Flow; Sodium

We examined renal sodium handling in rats with Hymann nephritis (HEN), an immunologically mediated model of nephrotic syndrome. Rats were studied 9-14 days following i.p. injection of anti-Fx1A antiserum. We previously demonstrated that HEN had a blunted volume expansion natriuresis (2% body weight isotonic saline infused over 5 min), excreting sodium at only half the rate of normal controls (CTL) despite similar increase in plasma atrial natriuretic peptide (ANP) concentration. Urinary excretion of cGMP accumulation by isolate glomeruli and inner medullary collecting duct (IMCD) cells in response to increasing concentration of ANP, and RNP (also called urodilatin). Results (fmol/mg prot/10 min) are means +/- SEM: [table: see text]. Basal accumulation of cGMP was not different among the groups, HEN rats hd reduced cGMP accumulation in response to ANP, and RNP. In binding studies using 125I-ANP, no difference in either density or affinity was found between CTL and HEN rats. Thus, there is a renal resistance to ANP in rats with HEN, which can be extended to other agents acting through the cGMP pathway. This resistance is not due to impaired binding of ANP, but to impaired accumulation of cGMP in responsive tissues, reflecting perhaps increased cGMP catabolism by phosphodiesterase. Such an observation may account for the altered sodium handling in nephrotic rats.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Drug Resistance; Immune Sera; Male; Natriuresis; Nephrotic Syndrome; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

We had a 20-year-old male patient of secondary aldosteronism similar to Bartter's syndrome, which had proved to be evident after the remission of nephrotic syndrome. In the patient, hypokalemic alkalosis and hyperreninemic hyperaldosteronemia were observed, although the blood pressure was normal. Hyperplasia of juxtaglomerular cells was observed and no abnormalities indicating either glomerulonephritis or renal artery stenosis were found; the pressor response to intravenously infused angiotensin (ang) II was markedly decreased; urinary prostaglandin (PG) E2, kallikrein and kinin excretion were elevated. The inhibition of PG synthesis with indomethacin decreased renal PG production and partially corrected both hypokalemia and pressor responsiveness to ang II. Thus, this case is considered to be a case of Bartter's syndrome. Contrary to the previously reported observations, the effective fractional chloride reabsorption rate in the renal distal tubules was normal (> 80%) and not changed by PG inhibition. Plasma atrial natriuretic peptide level was normal. An interaction between renin-angiotensin and PG systems appears to play a prior role in this case. To explain the pathophysiology, we have hypothesized an abnormal function of ang II receptor signal transduction which excessively stimulates PLA2, resulting in overproduction of PG synthesis in tissues.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Bartter Syndrome; Captopril; Chlorides; Cyclooxygenase Inhibitors; Dextrans; Humans; Hyperaldosteronism; Kidney; Kidney Tubules, Distal; Male; Nephrotic Syndrome; Prostaglandin Antagonists; Water-Electrolyte Balance

Lipoprotein(a) [LP(a)] is an independent risk factor for cardiovascular disease, and it has also been speculated that it promotes thrombosis. Recent studies have shown that patients with gross proteinuria have greatly increased plasma levels of Lp(a), but the genesis is obscure. In the present study, plasma Lp(a) levels were measured in 31 patients with nephrotic syndrome (NS), 24 patients with IgA nephropathy and 43 healthy control subjects. Lp(a) levels were significantly elevated in NS (median 49.0 mg/dl), in contrast to the control subjects and patients with IgA nephropathy (median 7.0 and 9.7 mg/dl, respectively). Plasma Lp(a) levels fell markedly in 10 of 10 NS patients after remission. In NS, Lp(a) levels correlated directly with serum cholesterol levels (P < 0.05) and indirectly with plasma orosomucoid levels (P < 0.05), but not with serum albumin, triglycerides, HDL cholesterol, urinary protein excretion or GFR. In addition, Lp(a) tended to be higher in NS patients with edema (median 54.3 mg/dl) than in patients without edema (19.0 mg/dl; P = 0.06). Nine NS patients were further evaluated with plasma ANP levels and urinary sodium excretion. Plasma Lp(a) correlated directly with ANP (P < 0.01) and indirectly with urinary sodium excretion (P < 0.05). Excellent correlations were found between Lp(a) and VLDL cholesterol and VLDL triglycerides, respectively, suggesting a close link between Lp(a) and triglyceride-rich lipoproteins in nephrosis.

Topics: Adrenal Cortex Hormones; Adult; Atrial Natriuretic Factor; Edema; Female; Humans; Lipids; Lipoprotein(a); Male; Nephrotic Syndrome; Remission Induction

Rat brain natriuretic peptide-45 (BNP-45) is a new cardiac hormone secreted into the circulation. In order to evaluate the pathophysiologic role of BNP in the nephrotic syndrome, we investigated the plasma levels and effects of BNP in adriamycin (ADR)-induced nephrotic rats. Plasma levels of BNP rose with time and more than doubled in 3 weeks after injection. Plasma levels of BNP correlated significantly with urinary protein excretion (UPrV) and urinary protein/creatinine ratio (UPrV/UcrV). When rat BNP-45 was injected as a bolus, hypotensive, diuretic, and natriuretic effects were completely abolished in nephrotic animals even at a high dose (2.0 nmol/kg), whereas the peptide produced marked UPrV with an increase in UPrV/UcrV. These results indicate that in ADR-induced nephrosis, BNP secretion from the heart is increased. Remarkable resistance to some hemodynamic and renal effects, while prompt proteinuric effects of BNP, may contribute to the sodium and water retention and urinary protein characteristic of this disorder.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Disease Models, Animal; Diuresis; Doxorubicin; Hemodynamics; Kidney; Male; Natriuresis; Nephrotic Syndrome; Nerve Tissue Proteins; Rats; Rats, Wistar

Experimental evidence is available to indicate that intrarenal mechanisms play a role in the impaired salt excretion of nephrotic syndrome by multiple and still incompletely defined mediators. It is documented herein that the gene encoding for cyclophilin-like protein (Cy-LP) is up-regulated in renal medulla from adriamycin (ADR)-treated rats as compared with control animals. In the cortex of rats with ADR nephrosis, no change in Cy-LP as compared with that in controls was found for the entire observation period. By contrast, in the medulla of nephrotic rats, Cy-LP gene expression was significantly higher than in controls. Values of urinary Na excretion were inversely correlated to Cy-LP mRNA expression levels. Because in ADR nephrosis a blunted natriuretic response to ANP has been previously reported, it was investigated whether ANP infusion modulated Cy-LP mRNA in the renal medulla. ADR-treated rats, but not control rats, infused for 1 h with ANP (1 microgram/kg.min) had a significant (P < 0.05) increase in medullary Cy-LP mRNA as compared with nephrotic animals receiving the vehicle alone. These findings might be taken to suggest that renal Cy-LP gene expression is positively modulated in nephrotic syndrome and parallels changes in sodium excretion.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Carrier Proteins; Doxorubicin; Gene Expression Regulation; Kidney Medulla; Male; Molecular Sequence Data; Natriuresis; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley; Sodium

1. In previous studies we found that albumin infusions caused only a modest natriuresis in the nephrotic syndrome, suggesting that hypovolaemia played no part in the sodium retention of these patients. However, this finding was inconclusive, since the hyperoncocity of the infused albumin probably opposed sodium excretion. 2. In the present study, we examined the effect of sustained (68 h) plasma volume expansion (+18%), by means of iso-oncotic albumin infusions, on renal function, blood pressure, humoral factors and sodium balance. 3. Plasma atrial natriuretic peptide levels increased almost threefold and renin-angiotensin system activity was suppressed. Glomerular filtration rate remained unchanged, whereas estimated renal plasma flow increased, resulting in a further decrease in filtration fraction. 4. The increase in plasma volume expansion was accompanied by a modest increase in sodium excretion, which, however, was less than the amount of sodium daily infused with the albumin solutions and consumed with the diet, so that net sodium was retained. 5. This observation supports the concept that an intrinsic renal defect causes the sodium retention in the nephrotic syndrome, and argues against the therapeutic use of albumin infusions.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Plasma Volume; Renin

Adriamycin-induced nephrotic syndrome in the rat is associated with a blunted natriuretic response to infusion of atrial natriuretic factor. To study the mechanism of renal hyporesponsiveness to the peptide in rats with experimental nephrosis, we evaluated the effects of the hormone on renal production of cGMP, the second messenger of the hormone. Baseline GFR and sodium excretion were lower in nephrotic as compared with normal controls. Infusion of synthetic rat atrial natriuretic factor (10 micrograms/kg/h) increased fractional sodium excretion by 7.3 +/- 2.4% in control rats but only by 1.4 +/- 0.5% in adriamycin-treated rats (P less than 0.05). However, the increments in urinary nucleotide excretion rate (UcGMP x V/GFR), in response to atrial natriuretic factor infusion, were comparable in control and nephrotic rats (control, 114.7 +/- 16.1 pmol/mL; adriamycin, 95.5 +/- 12.0 pmol/mL; P was not significant). The in vitro generation of cGMP in response to incremental doses of the hormone (10(-11) to 10(-6) M + 1 mM 3-isobutyl methyl xanthine) was of similar magnitude in isolated glomeruli derived from control (2.4 +/- 0.25 to 9.1 +/- 1.0 pmol/mg of protein) and nephrotic rats (2.9 +/- 0.2 to 10.3 +/- 1.0 pmol/mg of protein) and was not impaired in suspensions of medullary tissue derived from nephrotic rats (control, 8.4 +/- 0.6 to 14.2 +/- 1.2 pmol/mg of protein; adriamycin, 7.3 +/- 0.7 to 22.0 +/- 2.4 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Doxorubicin; In Vitro Techniques; Kidney Glomerulus; Kidney Medulla; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Inbred Strains

Atrial natriuretic peptide (ANP) is a cardiac hormone with natriuretic and diuretic effects. To better define the ANP hormonal system in the nephrotic syndrome, a condition associated with renal sodium retention, we undertook a study of glomerular ANP receptors in rats with puromycin aminonucleoside-induced nephrotic syndrome and in pair-fed controls. Nephrotic rats had significantly decreased serum albumin and total protein and significantly increased serum cholesterol, triglycerides and 24 hour urinary protein excretion. Plasma level of atrial natriuretic peptide was similar in both groups of rats. Competition binding inhibition studies in isolated glomeruli demonstrated one binding site in both groups of rats. The density of ANP binding sites in isolated glomeruli was similar in nephrotic and pair-fed rats while the binding affinity was increased significantly in the nephrotic rats. This is the first study to demonstrate alterations in renal ANP receptors in the nephrotic syndrome. Further studies will be necessary to determine whether alterations in glomerular ANP receptors contribute to renal sodium retention in the nephrotic syndrome.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; In Vitro Techniques; Kidney Glomerulus; Male; Nephrotic Syndrome; Protein Binding; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

The immunoreactivity of plasma and urine atrial natriuretic peptide (ANP) was measured in patients with renal disease and in healthy volunteers. The molecular forms of ANP in these subjects were estimated by gel permeation chromatography and reverse phase high performance liquid chromatography. No significant increase in plasma ANP was observed in patients with nephrotic syndrome or non-oliguric chronic renal failure compared to healthy volunteers. However, plasma ANP levels were significantly increased in patients on hemodialysis (normal 18.6 +/- 11.4 fmol/ml; hemodialysis 91.2 +/- 69.9 fmol/ml, p < 0.01). Chromatographic analyses revealed that plasma ANP consisted of only alpha-ANP or combined alpha- and gamma-ANP in healthy volunteers and in nephrotic patients, whereas beta-ANP frequently appeared in the plasma of both dialyzed and non-dialyzed chronic renal failure patients. Excreted forms, except in subjects free from renal disease where gamma-ANP may serve as a potential marker of glomerular injury in humans.

Topics: Adult; Atrial Natriuretic Factor; Chromatography, Gel; Chromatography, High Pressure Liquid; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Nephrotic Syndrome; Peptide Fragments; Radioimmunoassay; Renal Dialysis

Topics: Adult; Atrial Natriuretic Factor; Blood Volume; Catecholamines; Diuretics; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Humans; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Renin-Angiotensin System; Sulfonamides; Water-Electrolyte Balance

Blood volume, plasma concentrations of atrial natriuretic peptide, guanosine cyclic monophosphate (cGMP), angiotensin II, aldosterone and arginine vasopressin, and urinary excretion rate of prostaglandin E2, cGMP, sodium, and water were determined before and after intravenous administration of frusemide 0.75 mg/kg body-weight in nine patients with the nephrotic syndrome and 15 control subjects. The decrease in blood volume and the increase in urinary sodium and water excretion after fusemide were significantly reduced in the nephrotic patients compared with the controls. Atrial natriuretic peptide was reduced after frusemide both in patients (6.2 to 4.9 pmol/l, medians, P less than 0.05) and controls (5.9 to 4.8 pmol/l, P less than 0.01), but the nadir was delayed in the patients, and cGMP in plasma and urine was reduced only in the controls. The angiotensin II increase was delayed in the patients and aldosterone increased only in the controls. Basal urinary excretion of prostaglandin E2 was less in the nephrotic patients than in the controls (P less than 0.05), but after frusemide the prostaglandin E2 excretion rate increased in the patients (0.25 to 0.62 pmol/min, P less than 0.05), but not in the controls (0.46 to 0.39 pmol/min). In conclusion, reduced water and sodium excretion after frusemide in the nephrotic syndrome is accompanied by a diminished reduction of blood volume, a delayed decrease in atrial natriuretic peptide, and a blunted increase in angiotensin II and aldosterone compared with healthy subjects. Sodium excretion after frusemide may be more dependent on PGE2 production in nephrotic patients than in healthy subjects.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Volume; Body Water; Cyclic GMP; Dinoprostone; Female; Furosemide; Humans; Male; Middle Aged; Nephrotic Syndrome; Sodium

The levels of immunoreactive brain natriuretic peptide (ir-BNP) and immunoreactive atrial natriuretic peptide (ir-ANP) were evaluated by radioimmunoassay in both the atrium, ventricle and plasma of adriamycin-induced nephrotic rats and control rats. There was no difference in right and left atrial concentrations of ir-BNP, however, a higher right atrial concentration of ir-ANP was observed in nephrotic rats than in controls (p less than 0.01). The ventricular ir-BNP and ir-ANP were increased in nephrotic rats compared to controls (BNP: p less than 0.001, ANP: p less than 0.001). Cardiac BNPs were composed of pro-BNP (gamma-BNP) and its C-terminal 45-amino-acid peptide (BNP-45). The ratio of BNP-45/gamma-BNP in nephrotic rats was higher than that of controls in both atria and in the ventricle. Plasma ir-BNP and ir-ANP were significantly higher in nephrotic rats than in controls (BNP: p less than 0.001, ANP: p less than 0.001), and each level was negatively correlated with urinary sodium excretion in nephrotic rats (BNP: r = -0.84, p less than 0.001, ANP: r = -0.88, p less than 0.001). These results suggest that production and secretion of both BNP and ANP are concomitantly stimulated by a decreased renal ability to eliminate sodium and water, but this secretion is insufficient to induce effective natriuresis in nephrotic rats.

Topics: Animals; Atrial Natriuretic Factor; Doxorubicin; Heart Atria; Heart Ventricles; Male; Natriuresis; Natriuretic Peptide, Brain; Nephrotic Syndrome; Nerve Tissue Proteins; Rats; Rats, Inbred Strains; Sodium

Eight nonnatriuretic (daily Na excretion less than 50 mEq), 4 natriuretic (daily Na excretion greater than 50 mEq), and 4 steroid-responsive nephrotic patients, and 12 normal controls were studied with a 4-hour water immersion with measurements of electrolytes, plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) [corrected]. Four nonnatriuretic patients further received 25 g albumin infusion, with a subsequent 2-hour water immersion study. The results are as follows: (1) In the nonnatriuretic patients, the extremely low basal Na excretion rate, high PRA, and PA levels indicated a state of active Na retention. In spite of the water-immersion induced suppression of PRA and PA and a comparable magnitude of plasma ANP increment, the natriuretic response to water immersion was blunted in the nonnatriuretic patients. (2) In the natriuretic patients, water immersion resulted in a similar magnitude of natriuresis but a higher degree of plasma ANP increment in comparison to the normal controls. (3) Natriuretic and plasma ANP responses to water immersion were not different between the steroid-responsive patients and normal controls. (4) The increase in plasma ANP and the suppression of PRA and PA after 25 g albumin infusion did not result in natriuresis until the further suppression of PRA and PA and the further stimulation of plasma ANP by subsequent water immersion. The above results indicate that the natriuretic and plasma ANP responses to water immersion are related to the basal Na status in nephrotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Creatine; Female; Humans; Immersion; Male; Natriuresis; Nephrotic Syndrome; Renin; Serum Albumin; Sodium

In order to evaluate the pathophysiologic role of a free form of atrial natriuretic peptide (ANP) in the nephrotic syndrome, the plasma concentration of immunoreactive ANP was measured by radioimmunoassay using direct (unextracted) and extraction methods in adriamycin-induced nephrotic and normal control rats. The ir-ANP levels measured using unextracted or extracted plasma were representative of total and the free form of ANP, respectively. The plasma levels of total and the free form of ANP were significantly higher in nephrotic rats than in controls (p less than 0.01, p less than 0.001). However, plasma levels of the bound form of ANP, calculated by subtracting the free form of ANP from total ANP, were comparable between the two groups. The free form of ANP was inversely correlated with the daily urinary sodium excretion (r = -0.71, p less than 0.001) and plasma albumin (r = -0.83, p less than 0.001), and positively correlated with the daily urinary protein excretion (r = -0.85, p less than 0.001) in both control and nephrotic groups. Based on these results, the preferential increase in the free form of ANP in nephrotic rats is considered to be a compensatory phenomenon induced by the decreased renal ability to eliminate sodium and water. An increase in the free form of ANP may have some role in urinary protein excretion in the nephrotic syndrome.

Topics: Animals; Atrial Natriuretic Factor; Doxorubicin; Male; Nephrotic Syndrome; Protein Binding; Proteinuria; Rats; Rats, Inbred Strains; Serum Albumin

12 patients with the nephrotic syndrome (N.S.) and normal serum creatinine (less than 1.5 mg/dl) were investigated in a follow-up study over 10 days under diuretic treatment with piretanide (29 +/- 24 pg/ml). Clinical effects, parameters of renal clearance and hemodynamics, metabolic changes and the influence on vasoactive and volume dependent hormonal systems were studied. Piretanide markedly increased urine volume and electrolyte excretion (Vu +53%, UNa +24%, p less than 0.05, after 10 days treatment) but did not significantly alter glomerular filtration rate or renal blood flow. While baseline plasma renin activity was in the normal range and regularly stimulated (2.55 ng/ml x h to 7.7 ng/ml x h) plasma ANP values were elevated (152 +/- 107 pg/ml) at the start of the study and did not significantly change under piretanide treatment. This may be an indicator of sodium retention and a high plasma volume in the primary form of the nephrotic syndrome. Thereby piretanide did not significantly alter the intravascular space.

Topics: Adolescent; Adult; Aldosterone; Atrial Natriuretic Factor; Diuretics; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Nephrotic Syndrome; Sulfonamides

The physiological mechanism regulating secretion of alpha-human atrial natriuretic polypeptide (alpha hANP) was studied by measuring plasma alpha hANP (P alpha hANP) with radioimmunoassay during water immersion (WI). Twelve healthy volunteers and sixteen patients with nephrotic syndrome were immersed in water for 4 hours. During WI, alpha hANP level and urinary cGMP excretion (UcGV) increased significantly both in volunteers and patients, the urinary volume (UV) and urinary Na excretion (UNaV) also increased significantly. The mean peak values of alpha hANP and UcGV in volunteers were significantly lower than those in the patients, whereas the mean values of UV and UNaV in the former were significantly higher than those in the latter. The increase in alpha hANP level in volunteers correlated positively with the increase of UNaV, UV and UcGV during WI. The close correlations between the increased alpha hANP level and the increased UNaV, UV and UcGV was shown in the patients. These results suggest that alpha hANP is released into the circulation by acute central hypervolemia and plays a physiologically important role in maintaining water and electrolytes homeostasis in normal subjects and that the increased alpha hANP level in nephrotic syndrome makes compensatory regulation in water and electrolytes disorders.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Female; Humans; Immersion; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Sodium

1. The kidney taken from a rat rendered nephrotic by exposure to puromycin aminonucleoside retains sodium abnormally when perfused in isolation and has an abnormally low vascular resistance (J. D. Firth et al., Clin. Sci. 1989; 76, 387-95). In this study the relation of oxygen consumption to sodium reabsorption has been examined in the isolated nephrotic organ, which has also been exposed to a variety of natriuretic agents and to the effect of inhibition of metabolism by cooling, in an attempt to discern the transport process, or processes, responsible for abnormal tubular handling of sodium. In addition, the effects of three endogenous vasoconstrictors, noradrenaline, angiotensin II and endothelin, on the function of the isolated nephrotic kidney have been examined. 2. The ratio of mol of sodium reabsorbed by the tubules of the isolated nephrotic kidney to mol of oxygen consumed was reduced in comparison with the control kidney (means +/- SEM): 9.22 +/- 0.97 versus 15.43 +/- 1.55 (P less than 0.002). 3. In the presence of ouabain (1 mmol/l), acetazolamide (1 mmol/l), frusemide (200 mumol/l), the combination of these three agents together, hydroflumethiazide (100 mumol/l), benzamil (100 nmol/l) or atrial natriuretic peptide (1000 pmol/l), a lesser increment in sodium excretion was induced in the isolated nephrotic kidney than in the control kidney and the nephrotic organ continued to excrete less sodium in both absolute and fractional terms. 4. This suggests that enhanced tubular sodium reabsorption in the isolated nephrotic kidney does not depend upon abnormally increased activity of the Na+/K(+)-adenosine triphosphatase, bicarbonate-dependent sodium transport, Na+/K+/2Cl- co-transport, electrically neutral proportionate reabsorption of sodium and chloride (distal tubule), epithelial sodium channel (distal tubule) or atrial natriuretic peptide-sensitive sodium transport processes. 5. When isolated nephrotic kidneys and normal kidneys were cooled to 8-10 degrees C the handling of sodium became virtually identical in the two groups. On re-warming to 37 degrees C, the original differences in sodium handling between nephrotic and control kidneys were restored. This implies that the mechanism responsible for the abnormal tendency to retain sodium is temperature-sensitive; as yet it remains otherwise undefined. 6. The sensitivity of the renal vessels to noradrenaline, angiotension II and endothelin, as judged by the percentage reduction in perfusate flow rate

Topics: Acetazolamide; Amiloride; Angiotensin II; Animals; Atrial Natriuretic Factor; Furosemide; Kidney; Male; Nephrotic Syndrome; Norepinephrine; Organ Culture Techniques; Ouabain; Oxygen Consumption; Perfusion; Rats; Rats, Inbred Strains; Sodium; Temperature

To elucidate the pathophysiological role of atrial natriuretic peptide (ANP) in nephrotic syndrome, the plasma level of ANP and renal response to exogenous human alpha-ANP (alpha-hANP) were measured in untreated adult patients with idiopathic nephrotic syndrome (NS) and compared with those of normal volunteers (NL). The plasma concentration of immunoreactive ANP (ir-ANP) in NS (112 +/- 9.8 pg/ml, n = 9, mean +/- SE) was not significantly different from that in NL (98 +/- 8.0 pg/ml, n = 13). However, a significant positive correlation was observed between the plasma ir-ANP level and blood volume in NS (r = 0.714, p less than 0.05). In an infusion study with synthetic alpha-hANP (25 to 100 ng/kg/min), the urine flow rate increased from 0.67 +/- 0.08 to 7.11 +/- 1.08 ml/min in NL (n = 5, p less than 0.01) and from 0.64 +/- 0.16 to 2.88 +/- 0.70 ml/min in NS (n = 9, p less than 0.05) and the urinary sodium excretion increased from 115 +/- 16 to 466 +/- 62 microEq/min in NL (p less than 0.01) and from 51 +/- 8 to 207 +/- 58 microEq/min in NS (p less than 0.01). The absolute and percent changes in urine flow rate and the absolute change in sodium excretion were lower in NS (p less than 0.05) than in NL. The percent change in sodium excretion in NS did not differ from that in NL. In 2 patients with high plasma ir-ANP concentrations, however, infusion of ANP induced poor sodium excretion (59 and 95 microEq/min at 100 ng/kg/min ANP infusion, respectively). Hemodynamic and renal parameters such as blood pressure, pulse rate and creatinine clearance were similarly affected in both NL and NS. We also found that the urinary excretion of protein was significantly increased in NS (p less than 0.05) during infusion of alpha-hANP. Our data suggest that the plasma level of ir-ANP is regulated by blood volume status, and that the renal responsiveness to ANP, at least in part, contributes to water and sodium retention in NS.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Chlorides; Diuresis; Female; Heart Rate; Humans; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Osmolar Concentration; Urine

We followed the renal and hormonal effects of physiological intravenous infusions of atrial natriuretic factor (ANF) in 6 water-loaded patients with nephrotic syndrome and 7 healthy subjects. Two of the patients had impaired renal function, 3 had active sodium retention, and none took drugs. The ensuing natriuresis, increase in plasma and urinary cyclic guanosine monophosphate and suppression of the renin-aldosterone axis were similar in normals and nephrotics. In both groups, significant increases in filtration fraction (inulin/PAH clearance) were observed, and in the nephrotics, major increases also occurred in both the absolute and fractional urinary albumin excretion. The renal and hormonal responses to ANF are not impaired in the nephrotic syndrome.

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Infusions, Intravenous; Kidney; Male; Nephrotic Syndrome; Renin-Angiotensin System

Adriamycin (ADR) nephrosis and a model of unilateral ADR-induced proteinuria were produced in Sprague-Dawley (S.D.) rats to investigate the mechanism of sodium retention by the nephrotic kidney. Plasma volume, as measured by the dilution principle using radioiodinated serum albumin, was significantly higher in nephrotic animals than in control ones (NS: 69.61 +/- 15.02: control: 47.05 +/- 5.32 ml/kg: P less than 0.01). Similarly plasma levels of immunoreactive ANP (iANP) were significantly higher in nephrotic animals compared to controls (NS 104.22 +/- 36.41: control 59.94 +/- 20.88 pg/ml; P less than 0.05). Using the unilateral model we found a markedly reduced diuretic and natriuretic response to the infusion of synthetic rat atrial natriuretic peptide (ANP 1-28) in proteinuric kidney but not in contralateral kidney, despite a comparable increase in glomerular filtration rate. To explain the blunted diuresis and natriuresis in the presence of normal glomerular response to ANP, we investigated the possibility of an abnormality at post-glomerular level by studying ANP receptor density and affinity of the inner stripe of outer medulla and the inner medulla in ADR-and vehicle-treated rats. The inner stripe of outer medulla and the inner medulla receptor density and affinity were not significantly different in ADR rats as compared to animals given the vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Proteins; Disease Models, Animal; Doxorubicin; Glomerular Filtration Rate; Kidney Cortex; Male; Nephrotic Syndrome; Plasma Volume; Proteinuria; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Sodium

This study was designed to evaluate the renal effects of atrial natriuretic factor [ANF(8-33)] in rats with aminonucleoside (AMN)-induced nephrotic syndrome. AMN (100 mg/kg iv) was administered to adult female rats either 2 (AMN 2, n = 7), 4 (AMN 4, n = 7), 6 (AMN 6, n = 7), or 14 (AMN 14, n = 6) days before clearance experiments; untreated (UNT, n = 7) animals served as controls. During clearance experiments, rats were anesthetized with pentobarbital sodium. Protein excretion rates were similar between UNT and AMN 2 but increased stepwise in AMN 4, AMN 6, and AMN 14 rats. The glomerular filtration rate (GFR) was similar in UNT and AMN 2, lower in AMN 4 and AMN 14, and lowest in AMN 6 rats. Basal sodium excretion (UNaV) was not different among the five groups. An ANF primer (1.0 micrograms/kg iv) plus a constant infusion (0.1 micrograms.kg-1.min-1) for 1 h produced a significantly lower increase in UNaV in AMN 2 and AMN 14 than in UNT and was not natriuretic or diuretic in AMN 4 or AMN 6 rats. The ANF-induced increase in UNaV was similar between AMN 2 and AMN 14 rats. ANF had no effect on the GFR in any group. A higher ANF bolus (5.0 micrograms/kg iv) was then infused. This ANF bolus increased UNaV only in UNT and AMN 2 rats. Finally, a bolus of furosemide (4.0 mg/kg iv) was given; UNaV increased similarly in UNT, AMN 2, and AMN 14, and to a lesser extent in AMN 4 and AMN 6 rats. Thus, there is an attenuated natriuretic and diuretic response to ANF in rats with AMN-induced nephrotic syndrome. This altered responsiveness to ANF may contribute to the sodium and water retention characteristic of this disorder.

Topics: Animals; Atrial Natriuretic Factor; Female; Furosemide; Glomerular Filtration Rate; Kidney; Nephrotic Syndrome; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains

Atrial natriuretic peptide (ANP), angiotensin II (Ang II), and aldosterone (Aldo) in plasma and creatinine clearance (Ccr) were determined during basal conditions in 17 patients with the nephrotic syndrome and 20 control subjects. In addition, six of the patients were studied after seven remissions of the syndrome. In the nephrotic syndrome ANP was higher than in the control group (9.7 (median) versus 7.2 pmol/l, p less than 0.01), Ccr was lower (55 versus 99 ml/min, p less than 0.01). Angiotensin II and Aldo were the same in patients and control subjects. After remission of the syndrome ANP was reduced (11.2 to 5.4 pmol/l, n = 7, p less than 0.02) and Ccr increased (52 to 84 ml/min, n = 7, p less than 0.02), whereas Ang II and Aldo were unchanged. A significant, negative correlation was found between ANP and Ccr in the subgroup of patients in whom the syndrome remitted (Q = -0.547, n = 14, p less than 0.05). Atrial natriuretic peptide was not correlated to either Ang II or Aldo in either of the groups. It is concluded that patients with the nephrotic syndrome have elevated ANP, and it is suggested that a high ANP may be a compensatory phenomenon induced by a decreased renal ability to eliminate sodium and water.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Creatinine; Female; Humans; Male; Middle Aged; Nephrotic Syndrome; Remission, Spontaneous; Renin-Angiotensin System

To elucidate the abnormality of body fluid homeostasis that attends the nephrotic syndrome, we compared the atrial hormonal and renal excretory and vasomotor responses to water immersion of nephrotic patients (N = 10) with those of healthy controls (N = 9). Nephrotics exhibited depressed baseline levels of atrial natriuretic peptide (ANP, P less than 0.05) and lower rates of urine flow and sodium excretion (P less than 0.01). Although immersion-induced hypervolemia increased plasma ANP to equivalent levels (75 +/- 19 vs. 60 +/- 6 pg/ml), the disparity in corresponding urinary flow (5 +/- 1 vs. 13 +/- 2 ml/min, P less than 0.01) and sodium excretion (171 +/- 42 vs. 540 +/- 65 muEq/min, P less than 0.01) grew larger. In contrast, immersion caused an equivalent reduction of renal vascular resistance by 16 and 17%, respectively (P less than 0.01). Despite higher renal plasma flow and lower oncotic pressure of plasma, the glomerular filtration rate remained constant during immersion in both groups. Similar constancy of fractional clearances of dextrans of graded size suggests that immersion may have lowered the glomerular transcapillary hydraulic pressure difference (delta P). We conclude that renal vasomotor responsiveness to hypervolemia is preserved in nephrotics, but that the mediatory role of ANP in this response is uncertain. By contrast, diminished responsiveness of the distal nephron to the natriuretic action of endogenous ANP could contribute to edema formation in the nephrotic syndrome.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Body Fluids; Diuresis; Homeostasis; Humans; Immersion; Kidney; Middle Aged; Natriuresis; Nephrotic Syndrome; Plasma Volume

The aim of this study was to evaluate the renal response to atrial extracts (AE) and synthetic atrial natriuretic factor (ANF) in control rats and in rats with experimental nephrotic syndrome (NS). NS was obtained by a single intravenous injection of adriamycin (7.5 mg/kg). Bolus injection of AE from normal or NS rats resulted in marked increase of diuresis and natriuresis in bioassay control rats (AE from normal rats, urine flow rate, 14.87 +/- 2.94 to 186.18 +/- 55.86 microliters/min; Na excretion, 0.68 +/- 0.26 to 21.80 +/- 5.45 mu eq/min; AE from NS, urine flow rate, 13.49 +/- 4.30 to 167.14 +/- 51.44 microliters/min; Na excretion, 0.98 +/- 0.57 to 20.71 +/- 9.76 mu eq/min). In contrast, blunted diuretic (from 11.26 +/- 3.05 to 65.20 +/- 27.30 microliters/min) and natriuretic (from 0.58 +/- 0.15 to 4.52 +/- 1.59 mu eq/min) effect was observed when AE were injected in rats with NS. Injection of the vehicle in which AE were dissolved or ventricular extracts did not increase urinary flow rate or Na excretion in both control and NS animals. Bolus injection of synthetic ANF (Arg-101-Tyr-126) induced marked diuretic and natriuretic response in control but not in NS rats. Similar results were obtained when AE were infused by constant infusion in control or in NS bioassay rats. AE given by constant infusion induced comparable increase in glomerular filtration rate (GFR) over basal values both in control and NS animals (controls, 39%; NS rats, 40%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Function; Atrial Natriuretic Factor; Blood Pressure; Diuresis; Doxorubicin; Glomerular Filtration Rate; Male; Natriuresis; Nephrotic Syndrome; Potassium; Rats

Renal responses to atrial natriuretic peptide were examined in conscious dogs with congestive heart failure (tricuspid insufficiency) and in conscious rats with nephrotic syndrome (adriamycin). Heart-failure dogs displayed elevated atrial pressure and heart weights, blunted natriuresis to a saline load, and ascites. Nephrotic rats displayed proteinuria, hypoproteinemia, sodium retention, and ascites. In control animals, atrial natriuretic peptide increased absolute and fractional urine flow rate and urinary sodium excretion. Although atrial natriuretic peptide increased absolute and fractional urine flow rate and urinary sodium excretion in conscious heart-failure dogs and nephrotic rats, the responses were markedly blunted. In heart-failure dogs, infusion of atrial natriuretic peptide increased plasma concentrations of norepinephrine and epinephrine. In nephrotic rats, renal denervation reversed the blunted diuretic and natriuretic responses to atrial natriuretic peptide. Mean arterial pressure, glomerular filtration rate, and p-aminohippurate clearance were affected similarly by atrial natriuretic peptide in heart-failure dogs or nephrotic rats vs. control animals. Conscious congestive heart-failure dogs and conscious nephrotic rats have blunted diuretic and natriuretic responses to atrial natriuretic peptide.

Topics: Animals; Atrial Natriuretic Factor; Consciousness; Dogs; Dose-Response Relationship, Drug; Heart Failure; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Inbred Strains

Plasma levels of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), catecholamines and urinary prostaglandins (PG), as well as renal function were measured in children in the edematous state of the nephrotic syndrome before and after infusion of human serum albumin. Before albumin infusion, plasma levels of AVP, PRA, PA and noradrenaline (NA) and urinary excretion of PGE2, PGE-Met, PGF2 alpha were elevated. The mean value of plasma ANP was in the normal range. Albumin infusion produced a 36% increase in the calculated plasma volume. It was associated with a fivefold rise in the plasma level of ANP (31.6 +/- 22.6 vs. 151.4 +/- 52 fmol/ml mean, SD), and a significant fall in the levels of PRA, AVP, PA, and NA. Similarly, urinary concentration of PGE2, PGE-Met and PGF2 alpha fell. Urine flow, GFR, UNaV, FENa, and COsm increased significantly, while CH2O remained unchanged. The diuresis, natriuresis and GFR correlated with the level of plasma ANP, while urinary sodium excretion did not correlate with PA or NA levels. These findings suggest that ANP plays an important role in albumin induced natriuresis in children with nephrotic syndrome.

Topics: Adolescent; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Catecholamines; Child; Child, Preschool; Chlorides; Female; Glomerular Filtration Rate; Hormones; Humans; Male; Nephrotic Syndrome; Plasma Volume; Prostaglandins; Renin; Serum Albumin; Sodium; Vasomotor System

In six patients with nephrotic syndrome of various aetiology, the increase in absolute and fractional sodium excretion (FENa) after a bolus injection of 100 micrograms alpha-human atrial natriuretic peptide (ANP) was not different from the effect in normal healthy subjects at comparable sodium levels. Glomerular filtration rate rose in normals as well as in patients. In two patients, however, baseline sodium excretion was very low and the natriuretic response to ANP was proportionally blunted. The high baseline sodium reabsorption and blunted response to ANP may be explained as due either to an intrinsic renal defect or to a circulatory hypovolaemia. The finding of a low plasma ANP in these two patients, however, suggests involvement of a hypovolaemic component.

Topics: Adult; Atrial Natriuretic Factor; Diuretics; Female; Glomerular Filtration Rate; Hormones; Humans; Male; Natriuresis; Nephrotic Syndrome; Renin-Angiotensin System

The effect of volume changes on the plasma concentration of atrial natriuretic peptide (ANP) was investigated. In children with chronic renal failure predialysis plasma ANP was higher as compared to normal children and decreased significantly during hemodialysis. The decrease in plasma ANP correlated with body weight reduction. On the other hand, increase in plasma volume by infusion of albumin in children with nephrotic syndrome caused significant rise in plasma ANP and an increased natriuresis. Our data demonstrate that an expanded extracellular fluid volume and/or plasma volume appears to be a major stimulus for the release in ANP in children.

Topics: Adolescent; Albumins; Atrial Natriuretic Factor; Blood Volume; Child; Child, Preschool; Extracellular Space; Female; Humans; Kidney Failure, Chronic; Male; Natriuresis; Nephrotic Syndrome; Renal Dialysis

The natriuretic action of the atrial natriuretic factor (ANF) was studied in massively proteinuric, anti-natriuretic and edematous nephrotic rats with moderate impairment of renal function. Animals were distributed among four groups: NA----NR, NV----NR, NeA----NR and NA----NeR, where normal atrial (NA) or normal ventricular (NV) or "nephrotic" atrial (NeA) extracts were injected (----) into normal rats (NR) or nephrotic rats (NeR). Control (C) clearance measurements were made before iv injection of the extracts and at four 15-min intervals thereafter (E). Mean arterial pressure and glomerular filtration rate did not change consistently in all four groups from the C to the E period. However, during the first 15-min period after extract injection, statistically significant fractional natriuretic peaks of 332, 361 and 662% of preinjection control values were demonstrable for the NA----NR, NeA----NR and NA----NeR groups, respectively, but not for NV----NR. Following the natriuretic peak, natriuresis returned to control values for NA----NR, but remained above control levels for the NeA----NR and NA----NeR groups. We conclude that, since both the atrial extract from nephrotic rats injected into normal rats and the atrial extract from normal rats injected into nephrotic rats elicited marked natriuresis, the anti-natriuretic edematous condition observed in nephrotic animals cannot be attributed either to the absence of ANF in their atria or to the unresponsiveness of their kidneys to ANF.

Topics: Animals; Atrial Natriuretic Factor; Edema; Glomerular Filtration Rate; Kidney Diseases; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Inbred Strains; Sodium